rs12102203

Variant names:

• chr15-51499362-A-G
• rs12102203
• NM_001378457.1:c.3862T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-51499362-A-G
• chr15-51499362-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378457.1(DMXL2):​c.3862T>C​(p.Ser1288Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,613,468 control chromosomes in the GnomAD database, including 206,286 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18567 hom., cov: 32)
  • Exomes 𝑓: 0.51 (187719 hom.)
• Consequence: DMXL2 NM_001378457.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.269
• Publications: 43 publications found

Genes affected

DMXL2 (HGNC:2938): (Dmx like 2) This gene encodes a protein with 12 WD domains. Proteins with WD domains are involved in many functions including participation in signal transduction pathways. Participation of the encoded protein in regulation of the Notch signaling pathway has been demonstrated in vitro using several human cell lines (PMID:20810660). A gene encoding a similar protein is located on chromosome 5. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

DMXL2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 81

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• polyendocrine-polyneuropathy syndrome

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• hearing loss, autosomal dominant 71

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010027885).
• BP6: Variant 15-51499362-A-G is Benign according to our data. Variant chr15-51499362-A-G is described in ClinVar as Benign. ClinVar VariationId is 1255511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378457.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMXL2	NM_001378457.1	MANE Select	c.3862T>C	p.Ser1288Pro	missense	Exon 18 of 44	NP_001365386.1	H0YLM8
	DMXL2	NM_001378458.1		c.3862T>C	p.Ser1288Pro	missense	Exon 18 of 44	NP_001365387.1
	DMXL2	NM_001174116.3		c.3862T>C	p.Ser1288Pro	missense	Exon 18 of 43	NP_001167587.1	Q8TDJ6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMXL2	ENST00000560891.6	TSL:1 MANE Select	c.3862T>C	p.Ser1288Pro	missense	Exon 18 of 44	ENSP00000453267.2	H0YLM8
	DMXL2	ENST00000543779.6	TSL:1	c.3862T>C	p.Ser1288Pro	missense	Exon 18 of 43	ENSP00000441858.2	Q8TDJ6-3
	DMXL2	ENST00000251076.9	TSL:1	c.3862T>C	p.Ser1288Pro	missense	Exon 18 of 43	ENSP00000251076.5	Q8TDJ6-1

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74459 AN: 151852 Hom.: 18548 Cov.: 32

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.477

GnomAD2 exomes AF: 0.492 AC: 123222 AN: 250686 AF XY: 0.488

Gnomad AFR exome AF: 0.442

Gnomad AMR exome AF: 0.519

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.416

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.506 AC: 739086 AN: 1461498 Hom.: 187719 Cov.: 55 AF XY: 0.503 AC XY: 366016 AN XY: 727048

African (AFR) AF: 0.449 AC: 15021 AN: 33480

American (AMR) AF: 0.518 AC: 23160 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10190 AN: 26130

East Asian (EAS) AF: 0.443 AC: 17587 AN: 39696

South Asian (SAS) AF: 0.431 AC: 37181 AN: 86250

European-Finnish (FIN) AF: 0.552 AC: 29325 AN: 53150

Middle Eastern (MID) AF: 0.448 AC: 2585 AN: 5768

European-Non Finnish (NFE) AF: 0.517 AC: 574641 AN: 1111914

Other (OTH) AF: 0.487 AC: 29396 AN: 60390

GnomAD4 genome AF: 0.490 AC: 74527 AN: 151970 Hom.: 18567 Cov.: 32 AF XY: 0.489 AC XY: 36348 AN XY: 74280

African (AFR) AF: 0.444 AC: 18400 AN: 41436

American (AMR) AF: 0.501 AC: 7652 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1338 AN: 3470

East Asian (EAS) AF: 0.433 AC: 2231 AN: 5158

South Asian (SAS) AF: 0.425 AC: 2045 AN: 4816

European-Finnish (FIN) AF: 0.542 AC: 5719 AN: 10556

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35350 AN: 67948

Other (OTH) AF: 0.481 AC: 1016 AN: 2114

Alfa AF: 0.498 Hom.: 60343

Bravo AF: 0.488

TwinsUK AF: 0.507 AC: 1879

ALSPAC AF: 0.521 AC: 2009

ESP6500AA AF: 0.433 AC: 1902

ESP6500EA AF: 0.505 AC: 4332

ExAC AF: 0.492 AC: 59752

Asia WGS AF: 0.418 AC: 1452 AN: 3478

EpiCase AF: 0.504

EpiControl AF: 0.495

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 81 (1)
-	-	1	Hearing loss, autosomal dominant 71 (1)
-	-	1	Polyendocrine-polyneuropathy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.080	T
MetaRNN	Benign	0.0010	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.40	N
PhyloP100		0.27
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.027
Sift	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.030
MPC		0.26
ClinPred		0.0071	T
GERP RS		1.7
Varity_R		0.085
gMVP		0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12102203; hg19: chr15-51791559; COSMIC: COSV51842654; COSMIC: COSV51842654;